WO2008120003A1

WO2008120003A1 - Substituted piperidines for use in the treatment of bacterial infections

Info

Publication number: WO2008120003A1
Application number: PCT/GB2008/001182
Authority: WO
Inventors: Mark Cornebise; Folkert Reck
Original assignee: Astrazeneca Ab; Astrazeneca Uk Limited
Priority date: 2007-04-03
Filing date: 2008-04-03
Publication date: 2008-10-09

Abstract

The present invention relates compounds of Formula (I) or pharmaceutically acceptable salts thereof, which are believed to possess antibacterial activity.

Description

SUBSTITUTED PI PERIDINES FOR USE IN THE TREATMENT OF BACTERIAL INFECTIONS

Field of Invention

The present invention relates to novel piperidines, pharmaceutical compositions thereof, and methods of use. In addition, the present invention relates to therapeutic methods for the treatment of bacterial infections.

Background

The international health community continues to express serious concern that the evolution of antibacterial resistance will result in strains against which currently available antibacterial agents will be ineffective. For example, resistant strains of Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant coagulase-negative staphylococci (MRCNS), penicillin-resistant Streptococcus pneumoniae and multiple resistant Enterococcus faeciiim are both difficult to treat and difficult to eradicate. Consequently, in order to overcome the threat of widespread multi-drug resistant organisms, there is an on-going need to develop new antibiotics, particularly those with either a novel mechanism of action and/or containing new pharmacophoric groups.

Summary

In accordance with the present invention, the applicants have hereby discovered compounds that possess the ability to act as antimicrobials.

Accordingly the present invention provides compounds of Formula (I):

Formula (I) or pharmaceutically acceptable salts thereof.

The compounds of Formula (I) are believed to possess antibacterial activity, and are therefore useful for the treatment of bacterial infections. The present invention also provides processes for the preparation of compounds of Formula (I), pharmaceutical compositions containing them as the active ingredient, their use as medicaments, methods of using such compounds, and their use in the manufacture of medicaments for use in the treatment of bacterial infections in warm-blooded animals such as man.

Detailed Description of the Invention

The present invention provides a compound of Formula (I):

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein

A is selected from CH and N; D is selected from C-R⁵ and N, wherein at least one of A and D is carbon; E is selected from O, NH, and S, wherein: i) E is NH if R⁶ and R⁷ together form =0; and ii) E is O or S if R⁶ and R⁷ are each H; G is selected from O and S; X is selected from O and S;

R¹ is selected from H, halo, -CN, Ci-βalkyl, C₂-₆alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^la, -SR^la, -N(R^la)₂, -N(R^la)C(O)R^lb, -N(R^la)N(R^la)_2; -C(O)H, -C(O)R^lb, -C(O)₂R^la, -C(O)N(R^la)₂, -OC(O)N(R^la)₂, -N(R^la)C(O)₂R^la, -N(R^la)C(O)N(R^la)₂, -OC(O)R^lb, -S(O)R^lb, -S(O)₂R^lb, -S(O)₂N(R^la)₂, -N(R^la)S(O)₂R^lb, -C(R^la)=N(R^la), and -C(R^la)=N(OR^la), wherein said Ci-βalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R¹⁰;

R^la in each occurrence is independently selected from H, C^aUcyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R¹⁰;

R^lb in each occurrence is independently selected from

C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Q^alkyl, C_2-6alkenyl, C_2-6aU<ynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R¹⁰; R² is selected from H, halo, -CN, C_halky., C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^2a, -SR^2a, -N(R^2a)₂, -N(R^2a)C(O)R^2b, -N(R^2a)N(R^2a)₂, -C(O)H, -C(O)R^2b, -C(O)₂R^2a, -C(O)N(R^2a)₂, -OC(O)N(R^2a)₂, -N(R^2a)C(O)₂R^2a, -N(R^2a)C(O)N(R^2a)₂, -OC(O)R^2b, -S(O)R^2b, -S(O)₂R^2b, -S(O)₂N(R^2a)₂, -N(R^2a)S(O)₂R^2b, -C(R^2a)=N(R^2a), and -C(R^2a)=N(OR^2a), wherein said C^aUcyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R²⁰;

R^2a in each occurrence is independently selected from H, C^aUcyl, carbocyclyl, and heterocyclyl, wherein said C^aUcyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R²⁰;

R^2b in each occurrence is independently selected from Q-_δalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R²⁰; R³ is selected from H, halo, -CN,

C_2-6alkenyl, C₂.6alkynyl, carbocyclyl, heterocyclyl, -OR^3a, -SR^3a, -N(R^3a)₂, - -N(R^3a)N(R^3a)₂, -C(O)R^3b, , -C(O)N(R^3a)₂, -OC(O)N(R^3a)₂, -N(R^3a)C(O)₂R^3a, -N(R^3a)C(O)N(R^3a)₂, -OC(O)R^3b, -S(O)R^3b, -S(O)₂R^3b, -N(R^3a)S(O)₂R^3b, -C(R^3a)=N(R^3a), and -C(R^3a)=N(OR^3a), wherein said Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R³⁰; R^3a in each occurrence is independently selected from H, d-βalkyl, carbocyclyl, and heterocyclyl, wherein said C^alkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R³⁰;

R^3b in each occurrence is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R³⁰;

R⁴ in each occurrence is independently selected from halo, -CN, Q-βalkyl, C_2-6alkenyl,

C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^4a, -SR^4a, -N(R^4a)₂, -N(R^4a)C(O)R^4b , -C(O)H,

-C(O)R^4b, -C(O)₂R^4a, -C(O)N(R^4a)₂, -OC(O)N(R^4a)₂, -N(R^4a)C(O)₂R^4a, -N(R^4a)C(O)N(R^4a)₂,

-OC(O)R^4b, -S(O)R^4b, -S(O)₂R^4b, -S(O)₂N(R^4a)₂, -N(R^4a)S(O)₂R^4b, -C(R^4a)=N(R^4a), and

-C(R^4a)=N(OR^4a), wherein said Ci_-6alkyl, C_2-6alkenyl, C₂.₆alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R⁴⁰, or two R substituents on the 2 and 6 carbon atoms optionally may together form an ethylene bridge;

R^4a in each occurrence is independently selected from H, Q^alkyl, carbocyclyl, and heterocyclyl, wherein said C_1-6alkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R⁴⁰;

R^4b in each occurrence is independently selected from C^aHcyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R⁴⁰;

R⁵ is selected from H, halo, -CN, Ci-βalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -N(R^5a)N(R^5a)₂, -C(O)H, -C(O)R^5b,

-C(O)₂R^5a, -C(O)N(R^5a)₂, -OC(O)N(R^5a)₂, -N(R^5a)C(O)₂R^5a, -N(R^5a)C(O)N(R^5a)₂, -OC(O)R^5b,

-S(O)R^5b, -S(O)₂R^5b, -S(O)₂N(R^5a)₂, -N(R^5a)S(O)₂R^5b, -C(R^5a)=N(R^5a), and -C(R^5a)=N(OR^5a), wherein said Ci-βalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R⁵⁰;

R^Sa in each occurrence is independently selected from H, C_1-6alkyl, carbocyclyl, and heterocyclyl, wherein said C^aUcyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R⁵⁰;

R^5b in each occurrence is independently selected from Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R⁵⁰;

R⁶ and R⁷ are each hydrogen, or R⁶ and R⁷ together form =0;

R¹⁰ in each occurrence is independently selected from halo, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^10a, -SR^1Oa, -N(R^1Oa)₂, -N(R^10a)C(O)R^10b, -N(R^10a)N(R^10a)₂, -C(O)H, -C(O)R^10b, -C(O)₂R^10a, -C(O)N(R^{1 Oa})₂, -OC(O)N(R^10a)₂, -N(R^10a)C(O)₂R^10a, -N(R^10a)C(O)N(R^10a)₂, -OC(O)R^10b, -S(O)R^10b, -S(O)₂R^10b, -S(O)₂N(R^10a)₂, -N(R^10a)S(O)₂R^10b, -C(R^1Oa)=N(R^1Oa), and -C(R^10a)=N(OR^10a), wherein said Ci-βalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^a;

R^1Oa in each occurrence is independently selected from H, C^aHcyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^a;

R^1Ob in each occurrence is independently selected from Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^alkyl, C_2-6alkenyl, C_2-galkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^a; R²⁰ in each occurrence is independently selected from halo, -CN, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^20a, -SR^20a, -N(R^2Oa)₂, -N(R^20a)C(O)R^20b, -N(R^20a)N(R^20a)₂, -C(O)H, -C(O)R^20b, -C(O)₂R^20a, -C(O)N(R^20a)₂, -OC(O)N(R^20a)₂, -N(R^20a)C(O)₂R^20a, -N(R^20a)C(O)N(R^20a)₂, -OC(O)R^20b, -S(O)R^20b, -S(O)₂R^20b, -S(O)₂N(R^20a)₂, -N(R^20a)S(O)₂R^20b, -C(R^20a)=N(R^20a), and -C(R^20a)=N(OR^20a), wherein said Ci-βalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally substituted with one or more R^b;

R^20a in each occurrence is independently selected from H, C^aUcyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, carbocyclyl, and heterocyclyl are each, independently and optionally substituted with one or more R^b;

R^20b in each occurrence is independently selected from C^aUcyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^aHcyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^b; R³⁰ in each occurrence is independently selected from halo, -CN, C^aUcyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^30a, -SR^30a, -N(R^30a)_2s -N(R^30a)C(O)R^30b, -N(R^30a)N(R^30a)₂, -C(O)H, -C(O)R^30b, -C(O)₂R^30a, -C(O)N(R^30a)₂, -OC(O)N(R^30a)₂, -N(R^30a)C(O)₂R^30a, -N(R^30a)C(O)N(R3^10a)₂, -OC(O)R^30b, -S(O)R^30b, -S(O)₂R^30b, -S(O)₂N(R^30a)₂, -N(R^30a)S(O)₂R^30b, -C(R^3Oa)=N(R^3Oa), and -C(R^30a)=N(OR^30a), wherein said Ci-₆alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^c; R^30a in each occurrence is independently selected from H, Cμβalkyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^e;

R^3Ob in each occurrence is independently selected from C^alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^c; R⁴⁰ in each occurrence is independently selected from halo, -CN, C^alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^40a, -SR^40a, -N(R^4Oa)₂, -N(R^40a)C(O)R^40b, -N(R^40a)N(R^40a)₂, -C(O)H, -C(O)R^40b, -C(O)₂R⁴⁰³, -C(O)N(R^40a)₂, -OC(O)N(R^40a)₂, -N(R^40a)C(O)₂R^40a, -N(R^40a)C(O)N(R^40a)₂, -OC(O)R^40b, -S(O)R^40b, -S(O)₂R^40b, -S(O)₂N(R^40a)₂, -N(R^40a)S(O)₂R^40b, -C(R^40a)=N(R^40a), and -C(R^40a)=N(OR^40a), wherein said Ci-βalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^d;

R^40a in each occurrence is independently selected from H, C^alkyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^d;

R^40b in each occurrence is independently selected from Cμ_δalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci^alkyL C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally substituted with one or more R^d; R⁵⁰ in each occurrence is independently selected from halo, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^50a, -SR^50a, -N(R^50a)₂, -N(R^50a)C(O)R^50b, -N(R^50a)N(R^50a)₂, -C(O)H, -C(O)R^50b, -C(O)₂R^50a, -C(O)N(R^50a)₂, -OC(O)N(R^50a)₂, -N(R^50a)C(O)₂R^50a, -N(R^50a)C(O)N(R^50a)₂, -OC(O)R^50b, -S(O)R^50b, -S(O)₂R^50b, -S(O)₂N(R^50a)₂, -N(R^50a)S(O)₂R^50b, -C(R^50a)=N(R^50a), and -C(R^50a)=N(OR^50a), wherein said Cμβalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^e;

R^50a in each occurrence is independently selected from H, C^aUcyl, carbocyclyl, and heterocyclyl, wherein said C^aUcyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^e;

R^5Ob in each occurrence is independently selected from C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^e; R^a, R^b, R^c, R^d, and R^e in each occurrence are independently selected from halo, -CN, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^m, -SR^m, -N(R^ra)₂, -N(R^ra)C(O)Rⁿ, -N(R^m)N(R^m)₂, -C(O)H, -C(O)R", -C(O)₂R"¹, -C(O)N(R^m)₂, -OC(O)N(R^m)₂,

-N(R^m)C(O)₂R^m, -N(R^m)C(O)N(R^m)₂, -OC(O)R", -S(O)R", -S(O)₂R", -S(O)₂N(R^m)₂,

-N(R^m)S(O)₂R", -C(¹^)=N(R"¹), and -C(R^ra)=N(OR^ra);

R^m in each occurrence is independently selected from H and C^alkyl;

R" in each occurrence is

and n is selected from O, 1, 2, and 3.

In this specification the prefix C_x-y as used in terms such as C_x-yalkyl and the like (where x and y are integers) indicates the numerical range of carbon atoms that are present in the group; for example, Ci^alkyl includes Qalkyl (methyl), C₂alkyl (ethyl), Caalkyl (propyl and isopropyl) and C₄alkyl (butyl, 1-methylpropyl, 2-methylpropyl, and /-butyl).

As used herein the term "alkyl" refers to both straight and branched chain saturated hydrocarbon radicals having the specified number of carbon atoms. References to individual alkyl groups such as "propyl" are specific for the straight chain version only and references to individual branched chain alkyl groups such as 'isopropyl' are specific for the branched chain version only. For example, "Ci,6alkyl" includes, but is not limited to, groups such as methyl, ethyl, propyl, isopropyl, 1-methylpropyl, butyl, ^-butyl, pentyl, and hexyl. In one aspect, the term "alkyl" refers to methyl.

The term "alkenyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon double bond. For example, "C_2-6alkenyl" includes, but is not limited to, groups such as C_2-6alkenyl, C2_-4alkenyl, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, and 5-hexenyl.

The term "alkynyl" refers to both straight and branched chain hydrocarbon radicals having the specified number of carbon atoms and containing at least one carbon-carbon triple bond. For example, "C_2-6alkynyl" includes, but is not limited to, groups such as C_2-6alkynyl, C_2-4alkynyl, ethynyl, 2-propynyl, 2-methyl-2-propynyl, 3-butynyl, 4-pentynyl, and 5-hexynyl.

The term "halo" refers to fluoro, chloro, and bromo. In one aspect, the term "halo" refers to fluoro and chloro. In another aspect, the term "halo" refers to fluoro. The term "carbocyclyl" refers to a saturated, partially saturated, or unsaturated, mono or bicyclic carbon ring that contains 3-12 ring atoms, wherein one or more -CH₂- groups can optionally be replaced by a corresponding number of -C(O)- groups. In one aspect, the term "carbocyclyl" may refer to a monocyclic ring containing 3 to 6 ring atoms or a bicyclic ring containing 9 or 10 atoms. In another aspect, the term "carbocyclyl" may refer to a monocyclic ring containing 5 or 6 atoms. Illustrative examples of "carbocyclyl" include, but are not limited to, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1-oxocyclopentyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl. A particular example of a "carbocyclyl" group is phenyl.

The term "heterocyclyl" refers to a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 4-12 ring atoms of which at least one ring atom is selected from nitrogen, sulfur, and oxygen, and which may, unless otherwise specified, be carbon or nitrogen linked, wherein a -CH₂- group can optionally be replaced by a -C(O)-. Ring sulfur atoms may be optionally oxidized to form S-oxides. Ring nitrogen atoms may be optionally oxidized to form N-oxides. Illustrative examples of the term "heterocyclyl" include, but are not limited to, 1,3-benzodioxolyl, 3,5-dioxopiperidinyl, imidazolyl, indolyl, isoquinolone, isothiazolyl, isoxazolyl, morpholino, 2-oxopyrrolidinyl, 2-oxo-l,3-thiazolidinyl, piperazinyl, piperidyl, pyranyl, pyrazolyl, pyridinyl, pyrrolyl, pyrrolidinyl, pyrrolinyl, pyrimidyl, pyrazinyl, pyrazolyl, pyridazinyl, 4-pyridone, quinolyl, tetrahydropyranyl, thiazolyl, thiadiazolyl, thiazolidinyl, thienyl, thiomorpholino, thiophenyl, pyridine-N-oxide and quinoline-N-oxide. In one aspect of the invention the term "heterocyclyl" may refer to a saturated, partially saturated or unsaturated, monocyclic ring containing 5 or 6 atoms of which at least one atom is selected from nitrogen, sulfur, and oxygen, and may, unless otherwise specified, be carbon or nitrogen linked, and a ring nitrogen atom may be optionally oxidized to form an Ν-oxide.

Where a particular R group (e.g. R^la, R¹⁰, etc.) is present in a compound of Formula (I) more than once, it is intended that each selection for that R group is independent at each occurrence of any selection at any other occurrence. For example, the -N(R)₂ group is intended to encompass: 1) those -N(R)₂ groups in which both R substituents are the same, such as those in which both R substituents are, for example, C^aUcyl; and 2) those -N(R)₂ groups in which each R substituent is different, such as those in which one R substituent is, for example, H, and the other R substituent is, for example, carbocyclyl.

Unless specifically stated, the bonding atom of a group may be any suitable atom of that group; for example, propyl includes prop-1-yl and prop-2-yl.

The phrase "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician.

The term "leaving group" is intended to refer to groups readily displaceable by a nucleophile such as an amine nucleophile, and alcohol nucleophile, or a thiol nucleophile. Examples of suitable leaving groups include halo, such as chloro and bromo, and sulfonyloxy group, such as methanesulfonyloxy and toluene-4-sulfonyloxy.

The term "optionally substituted," indicates that substitution is optional and therefore it is possible for the designated group to be either substituted or unsubstituted. In the event a substitution is desired, any number of hydrogens on the designated group may be replaced with a selection from the indicated substituents, provided that the normal valency of the atoms on a particular substituent is not exceeded, and that the substitution results in a stable compound.

In one aspect, when a particular group is designated as being optionally substituted with "one or more" substituents, the particular may be unsubstituted. In another aspect, the particular group may bear one substituent. In another aspect, the particular substituent may bear two substituents. In still another aspect, the particular group may bear three substituents. In yet another aspect, the particular group may bear four substituents. In a further aspect, the particular group may bear one or two substituents. In still a further aspect, the particular group may be unsubstituted, or may bear one or two substituents. As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.

The term "protecting group" is intended to refer to those groups used to prevent selected reactive groups (such as carboxy, amino, hydroxy, and mercapto groups) from undergoing undesired reactions.

Illustrative examples of suitable protecting groups for a hydroxy group include, but are not limited to, an acyl group; alkanoyl groups such as acetyl; aroyl groups, such as benzoyl; silyl groups, such as trimethylsilyl; and arylmethyl groups, such as benzyl. The deprotection conditions for the above hydroxy protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively a silyl group such as trimethylsilyl may be removed, for example, by fluoride or by aqueous acid; or an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation in the presence of a catalyst such as palladium-on-carbon.

Illustrative examples of suitable protecting groups for an amino group include, but are not limited to, acyl groups; alkanoyl groups such as acetyl; alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, and ^-butoxycarbonyl; arylmethoxycarbonyl groups, such as benzyloxycarbonyl; and aroyl groups, such benzoyl. The deprotection conditions for the above amino protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a t-butoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric, phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium-on-carbon, or by treatment with a Lewis acid, for example boron trichloride). A suitable alternative protecting group for a primary amino group is, for example, a phthaloyl group, which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine or 2-hydroxyethylamine, or with hydrazine. Another suitable protecting group for an amine is, for example, a cyclic ether such as tetrahydrofuran, which may be removed by treatment with a suitable acid such as trifluoroacetic acid.

The protecting groups may be removed at any convenient stage in the synthesis using conventional techniques well known in the chemical art, or they may be removed during a later reaction step or work-up.

With reference to substituent R¹ for illustrative purposes, the following substituent definitions have the indicated meanings:

R^1a -N(RIa)₂ = _χ /%_1a

R¹³ O

-N(R^1a)C(O)R^1b = ) — N—L_R

R¹³ O

-N(R^1a)S(O)₂R^1b = J— N— S— R 1b

O

R^1a R¹³ -N(R^1a)N(R^1a)₂ = j— N-N-R¹³

The compounds discussed herein in many instances were named and/or checked with ACD/Name by ACD/Labs®.

Compounds of Formula (I) may form stable pharmaceutically acceptable acid or base salts, and in such cases administration of a compound as a salt may be appropriate. Examples of Acid addition salts include acetate, adipate, ascorbate, benzoate, benzenesulfonate, bicarbonate, bisulfate, butyrate, camphorate, camphorsulfonate, choline, citrate, cyclohexyl sulfamate, diethylenediamine, ethanesulfonate, fumarate, glutamate, glycolate, hemisulfate, 2-hydroxyethylsulfonate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, hydroxymaleate, lactate, malate, maleate, methanesulfonate, meglumine, 2-naphthalenesulfonate, nitrate, oxalate, pamoate, persulfate, phenylacetate, phosphate, diphosphate, picrate, pivalate, propionate, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, sulfate, tartrate, tosylate (p-toluenesulfonate), trifluoroacetate, and undecanoate. Examples of base salts include ammonium salts, alkali metal salts such as sodium, lithium and potassium salts, alkaline earth metal salts such as aluminum, calcium and magnesium salts, salts with organic bases such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, ornithine, and so forth. Also, basic nitrogen-containing groups may be quaternized with such agents as: lower alkyl halides, such as methyl, ethyl, propyl, and butyl halides; dialkyl sulfates such as dimethyl, diethyl, and dibutyl; diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl halides; arylalkyl halides such as benzyl bromide, and others. Non-toxic physiologically-acceptable salts are preferred, although other salts are also useful, such as in isolating or purifying the product.

The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion-exchange resin.

Compounds of Formula (I) have a chiral centre and may have multiple chiral centres and/or geometric isomeric centres (E- and Z- isomers), and it is to be understood that the invention encompasses all such optical, diastereoisomers and geometric isomers that possess antibacterial activity. The invention further relates to any and all tautomeric forms of the compounds of Formula (I) that possess antibacterial activity.

It is also to be understood that certain compounds of Formula (I) can exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which possess antibacterial activity.

Additional embodiments of the invention are as follows. These additional embodiments relate to compounds of Formula (I) and pharmaceutical salts thereof. Such specific substituents may be used, where appropriate, with any of the definitions, claims or embodiments defined hereinbefore or hereinafter.

A

In one aspect, A may be N.

D

In one aspect, D may be CH.

E

In one aspect, E may be O.

G

In one aspect, G may be O.

X

In one aspect, X may be O.

R¹

In one aspect, R¹ may be selected from H and C^aUcyl.

In another aspect, R¹ may be C^alkyL

In still another aspect, R¹ may be Ci_-3alkyl.

In yet another aspect, R¹ may be methyl.

In a further aspect, R¹ may be H.

R^

In one aspect, R may be H. B¹

In one aspect, R³ may be selected from halo, -CN, and -OR^3a; and R^3a may be Ci_-6alkyl.

In another aspect, R³ may be halo.

In still another aspect, R³ may be -CN.

In yet another aspect, R³ may be -OR^3a; and R^3a may be Ci_-6alkyl.

In a further aspect, R³ may be fluoro.

In still a further aspect, R³ may be methoxy.

In yet a further aspect, R³ may be selected from fluoro, -CN, and methoxy.

In one aspect, R⁴ may be selected from halo, C_halky!, and -OR^4a; and R^4a may be selected from H and C^alkyl.

In another aspect, R may be halo.

In still another aspect, R⁴ may be Ci^alkyL

In yet another aspect, R⁴ may be C^aUcyl.

In a further aspect, R⁴ may be -OR^4a; and R^4a may be selected from H and Ci-βalkyl.

In still a further aspect, R⁴ may be selected from halo, C_1-3alkyl, and -OR^4a; and R^4a may be selected from H and C_halky!. In yet a further aspect, R⁴ may be selected from fluoro, methyl, and -OR^4a; and R^4a may be selected from H and methyl.

In one aspect, R⁴ may be fluoro.

In another further aspect, R may be methyl

In still another aspect, R⁴ may be hydroxy.

In yet another aspect, R may be methoxy.

In a further aspect, the R⁴ substituent may be a substituent on the 3 -carbon or the 5-carbon.

In still a further aspect, two R⁴ substituents on the 2 and 6 carbon atoms optionally may together form an ethylene bridge.

E-

In one aspect, R⁶ and R⁷ are each hydrogen.

n

In one aspect, n may be 0, 1, or 2.

In another aspect, n may be 0 or 1, and wherein if n is 1,

R⁴ may be selected from halo, C_halky., and -OR^4a; and

R^4a may be selected from H and C^aUcyl.

In still another aspect, n may be 0.

In yet another aspect, n may be 1;

R⁴ may be selected from halo, C^aUcyl, and -OR^4a; and

R^4a may be selected from H and Ci_-6alkyl. A, D, E, G. R^ and R²

In one aspect, the compound of Formula (I) may be a compound of Formula (Ia):

Formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein X, R »1 , τ R»2 , - Rf-)3 , τ Rn4 , and n are as defined hereinabove.

In another aspect, the compound of Formula (I) may be a compound of Formula (Ib):

Formula (Ib)

or a pharmaceuticeutically acceptable salt thereof, wherein X, R , R , R , R , and n are as defined hereinabove.

A, D, E, G, X, R¹, R², R^a, R-. and n

In one aspect, the compound of Formula (I) may be a compound of Formula (Ia):

Formula (Ia) or a pharmaceutically acceptable salt thereof, wherein X may be O;

R¹ may be selected from H and Ci^alkyl; R² may be H;

R³ may be selected from halo, -CN, and -OR^3a; R^3a may be C_1-6alkyl;

R⁴ may be selected from halo, Ci_-6alkyl, and -OR^4a; R^4a may be selected from H and Ci_-6alkyl; and n may be 0 or 1.

In another aspect of the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof,

X may be O;

R¹ may be selected from H and Ci_-6alkyl;

R² may be H;

R³ may be selected from halo, -CN, and -OR^3a;

R^3a may be Ci^alkyl; and n may be 0. In still another aspect of the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof,

X may be O;

R¹ may be selected from H and C^aUcyl;

R² may be H;

R³ may be selected from halo, -CN, and -OR^3a;

R^3a may be Ci_-6alkyl;

R⁴ may be selected from halo, C^aHcyl, and -OR^4a;

R^4a may be selected from H and C^alkyl; and n may be 1.

In yet another aspect of the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof,

X may be O;

R¹ may be selected from H and methyl;

R² may be H;

R³ may be selected from fluoro, -CN, and methoxy;

R⁴ may be selected from fluoro, methyl, and methoxy; and n may be 0 or 1.

In a further aspect of the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof,

X may be O;

R¹ may be selected from H and methyl;

R² may be H;

R³ may be selected from fluoro, -CN, and methoxy;

R⁴ may be selected from fluoro, methyl, and methoxy; and n may be 1.

In still a further aspect of the compound of Formula (Ia), or a pharmaceutically acceptable salt thereof,

X may be O;

R¹ may be selected from H and methyl; R² may be H;

R³ may be selected from halo, -CN, and methoxy; and n may be 0.

Formula (Ib)

or a pharmaceutically acceptable salt thereof, wherein

X may be O;

R¹ may be H;

R² may be H;

R³ may be selected from halo, -CN, and -OR^3a;

R^3a may be Q-βalkyl; and n may be 0.

In still another aspect of the compound of Formula (Ib), or a pharmaceutically acceptable salt thereof,

X may be O;

R¹ may be H;

R² may be H;

R³ may be selected from -CN and -OR^3a; R^3a may be Ci_-6alkyl; and n may be 0.

In yet another aspect of the compound of Formula (Ib), or a pharmaceutically acceptable salt thereof,

X may be O;

R¹ may be H;

R² may be H;

R³ may be selected from -CN and methoxy; and n may be 0.

In another aspect, the present invention provides compounds of Formulas (I), and pharmaceutically acceptable salts thereof, as illustrated by the Examples, each of which provides a further independent aspect of the invention.

In still another aspect, the present invention provides a compound of Formula (I) selected from:

(3i?)-3-( {4-[(2,3-dihydro[ 1 ,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l - yl}methyl)-10-fluoro-2,3-dihydro-5H-[l,4]oxazino[2,3,4-z/]quinolin-5-one;

(3₁S)-3-({4-[(2,3-dihydro[l,4]dioxino[2,3-c]pyridin-7-ylmethyl)amino]piperidin-l-yl}methyl)-

10-fluoro-2,3-dihydro-5H-[l,4]oxazino[2,3,4-zj]quinolin-5-one;

(3i?)-5-oxo-3-[(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-δ][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)methyl]-2,3-dihydro-5H-[l,4]oxazino[2,3,4-zy]quinoline-10- carbonitrile;

(3_ιS)-5-oxo-3-[(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-ό][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)methyl]-2,3-dihydro-5H-[l,4]oxazino[2,3,4-?y]quinoline-10- carbonitrile;

(3R)- 10-methoxy-3 -[(4- { [(3-oxo-3 ,4-dihydro-2H-pyrido [3 ,2-b] [ 1 ,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)methyl]-2,3-dihydro-5H-[l,4]oxazino[2,3,4-//]quinolin-5- one; and

(3₁S)-10-methoxy-3-[(4-{[(3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]oxazin-6- yl)methyl]amino}piperidin-l-yl)methyl]-2,3-dihydro-5H-[l,4]oxazino[2,3,4-z/]qumolin-5- one, or a pharmaceutically acceptable salt thereof.

Biological Activity

The compounds of Formula (I) are of interest due to their antibacterial effects. The ability of the invention compounds disclosed herein to achieve an antibacterial effect may be demonstrated by the following tests.

Enzyme Potency Testing Methods

The compounds of Formula (I) were evaluated with regard to their ability to inhibit the ParC enzyme of Escherichia coll

The assay utilizes the ATPase activity of the ParE subunit of reconstituted Escherichia coli ParC/ParE tetramer protein. Inhibition of ATPase activity was monitored by reduced production of inorganic phosphate, a product of the ATPase reaction. Inorganic phosphate was quantified using the ammonium molybdate/malachite green-based detection systenxFor determination of IC50 values, assays were performed 384-well microtiter plates. Each well contained a dilution range of the compound dissolved in DMSO. In addition, each well contained: 20 mM Tris pH 8.0, 50 mM ammonium acetate, 0.16 mM ATP, 0.005% Brij-35, 8.0 mM magnesium chloride, 0.5 mM EDTA, 2.5% v/v glycerol, 5 mM dithiothreitol, 0.005 mg/mL sheared salmon sperm DNA, 0.5 nM E. coli ParC protein, 0.5 nM E, coli ParE protein. Final volume of assays was 30 μL. Reactions were incubated 24 hours at room temperature and then quenched with the addition of 45 μL malachite green reagent (Lanzetta, P. A., L. J. Alvarez, P. S. Reinach, and O. A. Candia (1979) Anal. Biochem. 100: 95-97) via a bulk reagent dispenser. Plates were incubated 3-5 minutes at room temperature, and then absorbance at 650 nM was measured using a Spectramax 384 plate reader.

Data for the compounds of the invention are depicted below in Table 1.

Table 1

Bacterial Susceptibility Testing Methods

Compounds may be tested for antimicrobial activity by susceptibility testing in liquid media in a 96 well format. Compounds may be dissolved in dimethylsulfoxide and tested in 10 doubling dilutions in the susceptibility assays. The organisms used in the assay may be grown overnight on suitable agar media and then suspended in a liquid medium appropriate for the growth of the organism. The suspension may be a 0.5 McFarland and a further 1 in 10 dilution may be advantageously made into the same liquid medium to prepare the final organism suspension in 100 μL. Plates may be incubated under appropriate conditions at 37 ⁰C for 24 hours prior to reading. The Minimum Inhibitory Concentration (MIC) is intended to refer to the lowest drug concentration able to reduce growth by 80% or more.

Compounds may be evaluated against organisms such as Gram-positive species, including Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, and Enterococcus faecium; and Gram-negative species including Haemophilus influenzae, Escherichia coli, Moraxella catarrhalis and Pseudomonas aeruginosa. Compounds of the present invention are believed to have MICs less than or equal to 8 μg/ml versus one or more of the organisms named above.

The compound of Example 1 had an MIC of 0.13 (mg/L) against Staphylococcus aureus and an MIC of 2.0 (mg/L) against Escherichia coli.

Thus, in one aspect there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use as a medicament.

In still another aspect, there is provided the use a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as man.

In yet another aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man.

In a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man.

In still a further aspect, there is provided the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man.

In another aspect, there is provided a method for treating a bacterial infection in a warmblooded animal such as man, said method including administering to said animal an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In still another aspect, there is provided a method for treating a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man, said method including administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In yet another aspect, there is provided a method for treating a bacterial infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man, said method including administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In a further aspect, there is provided a method for treating a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acinetohacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, in a warm-blooded animal such as man, said method including administering to said animal an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

In still a further aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection in a warm-blooded animal, such as man.

In another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man. In still another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating infections such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man.

In yet another aspect, there is provided a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in treating a bacterial infection, wherein the bacteria is of a genus selected from Aeromonas, Acmetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydophila, Citrobacter, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Haemophilus, Klebsiella, Legionella, Listeria, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Peptococci, Peptostreptococci, Prevotella, Proteus Salmonella, Pseudomonas, Serratia, Shigella, Stenotrophomonas, Streptococcus, and Staphylococcus, and Munnheimia, in a warm-blooded animal such as man.

In a further aspect, there is provided a pharmaceutical composition including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient

The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservative agents.

Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl /?-hydroxybenzoate; and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art.

Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finely powdered form or in the form of nano or micronized particles together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethyl or propyl ]> hydroxybenzoate; anti-oxidants such as ascorbic acid); coloring agents; flavoring agents; and/or sweetening agents such as sucrose, saccharine or aspartame.

Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil such as arachis oil, olive oil, sesame oil or coconut oil or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavoring and/or coloring agent.

The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol.

Compositions for administration by inhalation may be in the form of a conventional pressurized aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient.

For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 4 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

As stated above the size of the dose required for the therapeutic or prophylactic treatment of a particular disease state will necessarily be varied depending on the host treated, the route of administration and the severity of the illness being treated. Preferably a daily dose in the range of 1-50 mg/kg is employed. Accordingly, the optimum dosage may be determined by the practitioner who is treating any particular patient.

In any of the pharmaceutical compositions, processes, methods, uses, medicaments, and manufacturing features mentioned herein, any of the alternate aspects of the compounds of the invention described herein also apply. Process

If not commercially available, the necessary starting materials for the procedures such as those described herein may be made by procedures which are selected from standard organic chemical techniques, techniques which are analogous to the synthesis of known, structurally similar compounds, or techniques which are analogous to the described procedure or the procedures described in the Examples.

It is noted that many of the starting materials for synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or could be made from commercially available compounds using adaptations of processes reported in the scientific literature. The reader is further referred to Advanced Organic Chemistry, 5^th Edition, by Jerry March and Michael Smith, published by John Wiley & Sons 2001, for general guidance on reaction conditions and reagents.

It will also be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in compounds. The instances where protection is necessary or desirable are known to those skilled in the art, as are suitable methods for such protection. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Greene, Protective Groups in Organic Synthesis, published by John Wiley and Sons, 1991) and as described hereinabove.

Compounds of Formula (I) may be prepared in a variety of ways. The Processes, Schemes, and Examples shown below illustrate some methods for synthesizing compounds of Formula (I) and intermediates which may be used for the synthesis of compounds of Formula (I) (wherein A, D, E, G, X, R¹, R², R³, R⁴, R⁶, R⁷, and n, unless otherwise defined, are as defined hereinabove; and wherein PG denotes a protecting group). Where a particular solvent or reagent is shown in a Scheme or referred to in the accompanying text, it is to be understood that the chemist of ordinary skill in the art will be able to modify and/or replace that solvent or reagent as necessary. The Processes, Schemes, and Examples are not intended to present an exhaustive list of methods for preparing the compounds of Fonnula (I); rather, additional techniques of which the skilled chemist is aware may be also be used for the compounds' synthesis. The claims are not intended to be limited to the structures shown in the Processes, Schemes, and Examples. In one aspect, the present invention provides a process for preparing compounds of Formula (I), the process including reacting a compound of Formula (ID):

Formula (ID)

with a compound of Formula (IE)

Formula (IE); and

followed by reduction of the resulting compound with a suitable reducing agent; and thereafter if appropriate: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; and/or iii) forming a pharmaceutically acceptable salt.

Illustrative of the reducing agents suitable for use in the process described hereinabove for preparing compounds of Formula (I) are boron reducing agents, such as NaB(OAc)₃H.

Compounds of the Formula (IE) may be prepared following procedures described in the patent literature, such as those described in PCT Pub. No. WO 2004/058144 and WO 2008/003690. Scheme 1

Deprotection

Scheme 1 depicts a process for preparing compound (ID). Compound (IA) may be coupled with protected 4-aminopiperidme (IB). Reduction of the resulting compound with a suitable reducing agent provides compound (1C). Protecting groups suitable for such a reaction include if-butoxycarbonyl. Deprotection of the amino group of compound (1C) provides a compound of Formula (ID).

Scheme 2

(2B) (2C)

Another type of protected 4-aminopiperidines suitable for use in the process shown in Scheme 1 may be prepared following procedures published in the patent literature, such as those described in PCT Pub. Nos. WO 2006106326, WO 2006087543, WO 2005/068461 and WO 2005066176. Scheme 2 depicts the synthesis of a typical protected 4-aminopiperidine, which bears a silyl-protected hydroxy substituent, and of which the amino group is protected as an azide. The ring nitrogen of piperidine (2A) may be protected in the form of a carbamate, providing piperidine (2B). Protection of the hydroxy group of piperidine (2B) with a silyl protecting group provides piperidine (2C), the deprotection of the ring nitrogen of which provides protected 4-aminopiperidine (2D), which is a variation of protected 4- aminopiperidine (IB).

Scheme 3

(3B) (3A) (3C) (3D)

As depicted in Scheme 3, a hydroxy group may be introduced into the 3- position of the piperidine ring by reaction of epoxypiperidine (3A) with HBr to give trans 3-hydroxy-4- bromo piperidine (3C), which may be converted to the cis configuration (represented by compound (3D)) by reaction with sodium azide. Alternatively, the epoxide may be opened directly with sodium azide to provide the trans configuration, represented by compound (3B). The hydroxy group may be converted into an alkoxy group using standard alkylation procedures. For example, a hydroxy group may be converted into a methoxy group by alkylation with methyl iodide in the presence of a base, such as sodium hydride.

Scheme 4

(4D)

Scheme 4 depicts a typical process for introducing a fluoro substituent to the piperidine ring. Protected 4-Piperidone (4A) (for which suitable protecting groups include ^-butoxycarbonyl) may be converted to a silyl enolate by reaction with trimethylsilyl chloride (TMSCl) in the presence of a suitable base. The resulting silyl enolate (4B) may be reacted with a suitable fiuorinating agent, such as Selectfiuor® (sold by Air Products, Inc.), providing fluorinated compound (4C). The carbonyl group of compound (4C) may be converted to a protected nitrogen via reductive amination. If desired, the amino group may be further protected in a subsequent step, providing compound (4D).

Scheme 5

In another aspect, 3-hydroxy piperidine (5A) may be fluorinated with an appropriate fiuorinating agent such as diethylaminosulfur trifluoride (DAST), as depicted in Scheme 5, to provide fluorinated compound (5B). Scheme 6

(6A) (1A)

As shown in Scheme 6 suitable aldehyde for the first reductive animation step in Scheme 1 (as depicted in Scheme 1 by compound (IA)) may be obtained by oxidation of the corresponding alcohol (6A) with a suitable oxidizing agent, such as activated DMSO ("Swern oxidation"), or o-iodoxybenzoic acid (IBX).

Scheme 7

(7A) (6A)

Scheme 7 depicts a typical process for preparing alcohol (6A), in which quinolin-2(lH)-one (7A) may be alkylated with epichlorohydrin and treated with an appropriate base to provide compound (6A). Alternatively, the alkylation may be performed with cesium fluoride on celite instead of using a base.

(8B)

Quinolin-2(lH)-one 7(A) may be prepared by a number of procedures well known to the skilled chemist (see for example, The Chemistry of Ηeterocycles, Eicher and Ηauptmann, Wiley- VCH, ISBN 3-527-30720-6). For example, Scheme 8 depicts the preparation of quinolin-2(lH)-one (8C), which is a quinolin-2(lH)-one (7A) wherein R¹ is Η. Reaction of aniline (8A) with cinnamoylchloride in the presence of a suitable base, such as 2,6-lutidine provides compound (8B). Compound (8B) may cyclized by treatment with aluminum trichloride, which can also cleave the methyl ether.

In similar manner, cinnamoyl chloride may be substituted with E-ethoxyacryloyl chloride and cyclization of the intermediate E-ethoxyacryloylamide may be effected with a suitable acid, such as sulfuric, acid instead of aluminium trichloride (E. Baston et al, European Journal of Medicinal Chemistry 35 (2000) 931). Unsymmetrical substituted anilines generally lead to regioisomeric quinolin-2(lH)-one derivatives, which may be separated either by crystallization or may be converted to the corresponding 2-chloroquinoline (with, for example, phosphorusIII oxychloride), which may be separated by chromatography or by crystallization and may then be hydrolyzed back with refluxing hydrochloride acid to the single regioisomers of the quinolin-2(lH)-ones.

Scheme 9

Another method for preparing quinolin-2(lH)-one 7(A) is depicted in Scheme 9. Substituted benzene (9A) may be coupled with methacrylate (9B) under typical Ηeck coupling conditions, forming compound (9C). Intramolecular amide bond formation of an appropriately set-up cis unsaturated system provides quinolin-2(lH)-one 7(A). Isomerization of a trans double bond may be performed thermically or photochemically under uv light.

In another aspect, the carbon-carbon bond formation may be performed via Sonogashira Coupling, providing alkyne intermediate (9D), which may be partially hydrogenated to a cis double bond under Lindlar conditions, providing compound (9E).

Scheme 10

4-Substituted quinolin-2(lH)-one (7A), suitable for alkylation as depicted in Scheme 7, may be prepared by acylation of aniline (10A), or aza analogs thereof, with ethylaceto acetate or derivatives thereof, in the presence of base, followed by cyclization of the resulting compound (10B) under acidic conditions. Such a process is depicted in Scheme 10.

Scheme 11

(11A) (11B)

Substituents at R » 1 , R τ>2 or R may advantageously be introduced by conversion of a more stable substituent. For example, quinolin-2(lH)-one (HB), substituted in the R3 position with a cyano group, may be obtained from bromo substituted quinolin-2(lH)-one (1 IA) by reaction with a cyanide such as zinc cyanide or copper cyanide, as depicted in Scheme 11. A palladium catalyst may be advantageously used for this reaction. An example of an amino protecting group suitable for use in such a reaction is t-butoxycarbonyl.

When an optically active form of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure enantiomer as a starting material, or by resolution of a mixture of the enantiomers or diastereomers of the final products or chiral intermediates using a standard procedure. The resolution of enantiomers may be achieved by chromatography on a chiral stationary phase, such as a Chiralpak AD column. Consideration should to be given to solubility as well as resolution. Alternatively, resolution may be obtained by the preparation and selective crystallization of a diastereomeric salt of a chiral intermediate or chiral product with a chiral acid, such as camphersulfonic acid. Alternatively, a method of stereoselective synthesis may be employed, for example by using a chiral variant of a protection group, a chiral catalyst or a chiral reagent where appropriate in the reaction sequence.

Enzymatic techniques may also be useful for the preparation of optically active compounds and/or intermediates.

Examples

The invention is now illustrated by but not limited to the following Examples, for which, unless otherwise stated:

(i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids by filtration; (ii) temperatures are quoted as ⁰C; operations were carried out at room temperature, that is typically in the range 18-26 ⁰C and without the exclusion of air unless otherwise stated, or unless the skilled person would otherwise work under an inert atmosphere; (iii) column chromatography (by the flash procedure) was used to purify compounds and was performed on Merck Kieselgel silica (Art. 9385) unless otherwise stated; (iv) in general, the course of reactions was followed by TLC, ΗPLC, or LC/MS and reaction times are given for illustration only; yields are given for illustration only and are not necessarily the maximum attainable; (v) the structure of the end-products of the invention was generally confirmed by NMR and mass spectral techniques. Proton magnetic resonance spectra were generally determined in DMSOd₅ unless otherwise stated, using a Bruker DRX-300 spectrometer or a Bruker DRX-400 spectrometer, operating at a field strength of 300 MHz, or 400 MHz, respectively. In cases where the NMR spectrum is complex, only diagnostic signals are reported. Chemical shifts are reported in parts per million downfield from tetramethylsilane as an internal standard (δ scale) and peak multiplicities are shown thus: s, singlet; d, doublet; dd, doublet of doublets; dt, doublet of triplets; dm, doublet of multiplets; t, triplet, m, multiplet; br, broad. Fast-atom bombardment (FAB) mass spectral data were generally obtained using a Platform spectrometer (supplied by Micromass) run in electrospray and, where appropriate, either positive ion data or negative ion data were collected or using Agilent 1100 series LC/MSD equipped with Sedex 75ELSD, and where appropriate, either positive ion data or negative ion data were collected. The lowest mass major ion is reported for molecules where isotope splitting results in multiple mass spectral peaks (for example when chlorine is present). Reverse Phase HPLC was carried out using YMC Pack ODS-AQ (100x20 mmID, S-5μ particle size, 12 nm pore size) on Agilent instruments;

(vi) each intermediate was purified to the standard required for the subsequent stage and was characterized in sufficient detail to confirm that the assigned structure was correct; purity was assessed by HPLC, TLC, or NMR and identity was determined by infra-red spectroscopy (IR), mass spectroscopy or NMR spectroscopy as appropriate; and

(vii) the following abbreviations may be used:

TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; MPLC is medium pressure liquid chromatography; NMR is nuclear magnetic resonance spectroscopy; DMSO is dimethylsulfoxide; CDCl₃ is deuterated chloroform; MeOD is deuterated methanol, i.e. D₃COD; MS is mass spectroscopy; ESP (or ES) is electrospray; EI is electron impact; APCI is atmospheric pressure chemical ionization; THF is tetrahydrofuran; DCM is dichloromethane; MeOH is methanol; DMF is dimethylformamide; EtOAc is ethyl acetate; LC/MS is liquid chromatography/mass spectrometry; h is hour(s); min is minute(s); d is day(s); MTBD is N-methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene; TFA is trifluoroacetic acid; v/v is ratio of volume/volume; Boc denotes t-butoxycarbonyl; Cbz denotes benzyloxycarbonyl; Bz denotes benzoyl; atm denotes atmospheric pressure; rt denotes room temperature; mg denotes milligram; g denotes gram; μL denotes microliter; mL denotes milliliter; L denotes liter; μM denotes micromolar; mM denotes millimolar; M denotes molar; N denotes normal; nm denotes nanometer.

Example 1

3-(i4-r(2,3-DihvdrorL41dioxinor2,3-glpyridm-7-ylmethyl)aminolpiperidin-l-yl}methyl)-10- fluoro-23-dihydro-5H-[l,41oxazino[2,3,4-z7^'lquinolin-5-one

A mixture of 3-[(4-aminopiperidin-l-yl)methyl]-10-fiuoro-2,3-dihydro-5H-

[l,4]oxazino[2,3,4-z/]quinolin-5-one (Intermediate 1, 30 mg, 0.095 mmol) and 2,3- dihydro[l,4]dioxmo[2,3-c]pyridine-7-carbaldehyde (PCT Pub. No. WO 2004/058144, 15.6 mg, 0.095 mmol) in chloroform : methanol (1:1, 6 mL) was heated over freshly activated 3 A molecular sieves at 7O⁰C for 2 hours. The reaction mixture was cooled to room temperature, and sodium triacetoxy borohydride (60 mg, 0.28 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The mixture was purified by chromatography on silica gel with dichloromethane/ methanol (6:1). Fractions containing product were combined and concentrated to dryness. The residue was taken up in dichloromethane/ diethyl ether (1:2, 10 mL), and HCl in diethyl ether (2M, -0.10 mL) was added. The mixture was concentrated to dryness under reduced pressure, codistilled two times with dichloromethane (2x 15 mL) and titurated from ether to give the bis hydrochloride salt of the product as a mixture of enantiomers in the form of a colorless solid, 39 mg (76%), mp >240°C.

MS TES): 467 (MH⁺) for C₂₅H₂₇FN₄O₄

¹H-NMR fPMSO-d^ δ: 2.15 (m, 2H); 2.31 (m, 2H); 3.05 (m, 3H); 3.30 (m, IH); 3.48 (m, IH); 3.93 (m, 2H); 4.15-4.25 (m, 3H); 4.34 (m, 2H); 4.39 (m, 2H); 5.16 (m, IH); 5.35 (m, IH); 6.64 (d, IH); 7.24 (m, IH); 7.27 (s, IH); 7.42 (dd, IH); 8.00 (d, IH); 8.21 (s, IH); 9.76 (brs, 2H); 10.35 (brs, IH). Intermediate 1

3-[(4-Ammopiperidin-l-yl)methyl1-10-fluoro-2,3-dilivdro-5H-[L41oxazino[2.3,4-z7]quinolin- 5-one

A solution of tert-butyl {l-[(10-fluoro-5-oxo-2,3-dihydro-5H-[l,4]oxazino[2,3,4-//]quinolin- 3 -yl)methyl]piperidin-4-yl} carbamate (Intermediate 2, 70 mg, 0.168 mmol) in dichloromethane (2 niL) was treated at O⁰C with trifluoroacetic acid (1 mL). After two hours, the solvent was removed under reduced pressure and the residue was codistilled two times with dichloromethane. The residue was taken up in dichloromethane (20 mL) and saturated sodium hydrogencarbonate solution (10 mL). The pΗ of the aqueous phase was adjusted to ~pΗ 10 with 15% aqueous sodium hydroxide. The organic phase was separated, the aqueous phase extracted with dichloromethane three times (3x 20 mL), and the combined organic phases were dried over sodium sulfate to give the product as a colorless oil, 30 mg (56%). MS (ES): 318 (MH⁺) for C₁₇H₂₀FN₃O₂

¹H-NMR (DMSO-dfi) δ: 1.43 (m, 2H); 1.81 (m, 2H); 2.15 (ddd, IH); 2.26 (ddd, IH); 2.35 (dd, IH); 2.58-2.69 (m, 2H); 2.88 (m, IH); 3.16 (m, IH); 4.07 (m, IH); 4.98 (m, IH); 6.60 (d, IH); 7.09 (dd, IH); 7.28 (dd, IH); 7.88 (d, IH).

Intermediate 2 fert-Butyl ( 1 -rri 0-fluoro-5-oxo-2.3 -dihvdro-5H-r 1.41 oxazino [2,3 ,4-zVl quinolin-3 -vD methvπpiperidm-4-yll carbamate

A mixture of 10-fiuoro-5-oxo-2,3-dihydro-5H-[l,4]oxazino[2,3,4-?y]quinoline-3-carbaldehyde

(Intermediate 3, 242 mg, ~ 1 mmol) and tert-butyl piperidin-4-ylcarbamate (416 mg, 2.08 mmol) in chloroform/ methanol (1:1, 10 mL) was heated over freshly activated 3 A molecular sieves at 7O⁰C for 3 hours. The reaction mixture was cooled to room temperature, and sodium triacetoxy borohydride (660 mg, 3.11 mmol) was added. The resulting reaction mixture was stirred at room temperature for one hour and then was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. Chromatography on silica gel with hexanes/ acetone (2:1) gave the product as a colorless oil, 70 mg (16%).

MS (ES): 418 (MH⁺) for C₂₂H₂₈FN₃O₄

¹H-NMR (DMSO-AQ δ: 1.47 (s, 9H); 1.66 (m, 2H); 1.92 (m, 2H); 2.09-2.20 (m, 2H); 2.35

(m, IH); 2.80 (m, IH); 4.40 (m, IH); 4.50 (m, IH); 4.70 (m, IH); 6.48-6.52 (m, 2H); 6.64

(dd, IH); 6.93 (d, IH). Intermediate 3

10-Fluoro-5-oxo-2,3-dihvdro-5H-[^'l,41oxazinor2.3,4-z7lquinolme-3-carbaldehvde o-Iodoxybenzoic acid (761 mg, 2.7 mmol) was dissolved in dimethylsulfoxide (DMSO) (5 mL) at room temperature. 10-Fluoro-3-(hydroxymethyl)-2,3-dihydro-5H-[l,4]oxazino[2,3,4- 7_/"]quinolin-5-one (Intermediate 4, 0.426 g, -1.44 mmol), dissolved in DMSO (5 mL) was added and the reaction mixture was stirred over night. Water (5 mL) was added, the colorless precipitate was removed by filtration and the filtrate was extracted three times with dichloromethane (3x 40 mL). The combined organic phases were dried over sodium sulfate and the solvent was removed under reduced pressure. Chromatography on silica gel with hexanes/ acetone (3:2) gave the crude product as a colorless oil (242 mg). MS (ES): 234 (MH⁺) for Ci₂H₈FNO₃

Intermediate 4

10-Fluoro-3-(hvdroxymethyl)-2,3-dihvdiO-5H-fl,4]oxazmor2,3,4-;y|quinolm-5-one

A mixture of 7-fluoro-8-hydroxyquinolin-2(lH)-one (Intermediate 5, 590 mg, 3.3 mmol), epichlorohydrin (2.6 mL, 33 mmol) and catalytic piperidine (5μL) in dioxane/ dimethylformamide (DMF) (2:1, 15 mL) was heated at 85⁰C for 16 hours. The solvent was removed under reduced pressure, and the residue was codistilled with ethanol twice.

Chromatography on silica gel with ethyl acetate gave the crude product as a colorless solid

(426 mg). This material contained ~ 20% of l l-fluoro-3-hydroxy-3,4-dihydro-2H,6H-

[l,4]oxazepino[2,3,4-z/]qumolin-6-one. The crude product was used for the next step without further purification.

MS (ES): 236 (MH⁺) for C₁₂Hi₀FNO₃

¹H-NMR (DMSO-d^ δ: 3.36 (ddd, IH); 3.49 (ddd, IH); 4.11 (dd, IH); 4.75 (m, IH); 4.80

(m, IH); 5.32 (dd, IH); 6.58 (d, IH); 7.16 (dd, IH); 7.35 (dd, IH); 7.92 (d, IH).

Intermediate 5

7-Fluoro-8-hvdroxyquinolin-2(lH)-one

A mixture of (2£)-N-(3-fluoro-2-methoxyphenyl)-3-phenylacrylamide (Intermediate 6, 6.2 g, 23 mmol) and aluminium trichloride (18.3 g, 137 mmol) in chlorobenzene (150 mL) was heated to 120 ⁰C for two hours. It was cooled to room temperature and poured onto ice. The precipitate was collected by filtration and washed with ethyl acetate (20 mL) to give the product as a slightly purple solid, 590 mg (14%). MS CES): 180 (MH⁺) for C₉H₆FNO₂

¹H-NMR (DMSO-(U δ: 6.42 (d, IH); 7.02 (dd, IH); 7.16 (dd, IH); 7.83 (d, IH); 10.30 (s,

IH); 10.88 (s, IH).

Intermediate 6

(^"2-E)-N-(3-Fluoro-2-methoxyphenylV3-phenylacrylamide

A mixture of (3-fluoro-2-methoxyphenyl)amine (5 g, 35.4 mmol) and 2,6-lutidine (7.4 mL, 64 mmol) in dichloromethane (20 mL) was treated at O⁰C dropwise with a solution of cinnamoylchloride (7.08 g, 42.5 mmol) in dichloromethane (30 mL). The reaction mixture was allowed to reach room temperature and was stirred over night. It was quenched with potassium phosphate buffer (50 mL, IM, pH 7) and stirred for 15 minutes. Dichloromethane was removed under reduced pressure and it was extracted with ethyl acetate. The organic phase was washed with phosphate buffer (like above, 100 mL), dried over sodium sulfate and concentrated to dryness. The residue was crystallized from ethyl acetate/ hexanes and then recrystallized from hexanes to give the product as colorless solid (6.21 g, 65%), mp 8O⁰C. MS (ESP^; 272 (MH⁺) for C₁₆H₁₄FNO₂

¹H-NMR (DMSO-AO δ: 3.88 (s, 3H); 6.97-7.12 (m, 2H); 7.23 (d, IH); 7.38-7.48 (m, 3H); 7.56-7.65 (m, 3H); 8.05 (m, IH); 9.61 (s, IH).

Example 2

5-Oxo-3-((4-((3-oxo-3.4-dihvdro-2H-pyridor3,2-bl[l,41oxazin-6-yl)methylamino)piperidin-l- yl)methylV3,5-dihvdro-2H-[L4]oxazinor23,4-ii]quinoline-10-carbonitrile, Enantiomer 1 A mixture of 3-((4-aminopiperidin-l-yl)methyl)-5-oxo-3,5-dihydro-2H-[l,4]oxazino[2,3,4- ij]quinoline-10-carbonitrile, Enantiomer 1 (Intermediate 7, 60 mg, 0.18 mmol) and 3-oxo- 3,4-dihydro-2H-pyrido[3,2-έ][l,4]oxazine-6-carboxaldehyde (WO 2004/058144) (33 mg, 0.18 mmol) in TΗF (5 mL) was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (98 mg, 0.46 mmol) was added and the mixture stirred for four hours. The reaction was quenched with methanol and the mixture concentrated under reduced pressure. The residue was chromatographed on silica gel eluting first with a gradient of 0 to 10% methanol in dichloromethane to give 42 mg (47%) of the title compound as a tan solid. MS (ES): 487 (M+Η⁺) for C₂₆H₂₆N₆O₄

¹H-NMR (DMSO-d_e) δ: ppm 1.23 - 1.37 (m, 2H), 1.80 (t, 2H), 1.89 (s, 2H), 1.99 (t, IH), 2.11 (t, IH), 2.25 (dd, IH), 2.74 (d, IH), 3.01 (d, IH), 3.75 (s, 2H), 4.25 (dd, IH), 4.60 (s, 2H), 4.83 (d, IH), 4.92 (d, IH), 5.74 (s, IH), 6.79 (d, IH), 7.01 (t, IH), 7.27 - 7.33 (m, IH), 7.42 - 7.47 (m, IH), 7.48 - 7.54 (m, IH), 8.00 (d, IH), 11.19 (br s, IH).

Example 3

5-Oxo-3-(('4-f(3-oxo-3.4-dihvdro-2H-pyridor3,2-b1[1.41oxazin-6-yl)methylammo)piperidin-l- yl)methyl)-3,5-dihvdro-2H-[l,41oxazino[2,3,4-ij]quinoline-10-carbonitrile. Enantiomer 2

3-((4-Aminopiperidin~ l-yl)methyl)-5-oxo-3,5-dihydro-2H-[ 1 ,4]oxazino[2,3 ,4-ij]quinoline- 10- carbonitrile, Enantiomer 2 (Intermediate 8, 50 mg, 0.15 mmol) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-έ][l,4]oxazine-6-carboxaldehyde (27 mg,

0.15 mmol) and sodium triacetoxyborohydride (82 mg, 0.39 mmol) using a procedure similar to the one described for the synthesis of Example 2 to give 43 mg (0.09 mmol, 47%) of the title compound as a tan solid.

MS (ES^: 487 (M+Η⁺) for C₂₆H₂₆N₆O₄

¹H-NMR (300 MHz. DMSO-d^ δ: ppm: 1.16 - 1.31 (m, 2H), 1.68 - 1.82 (m, 2H), 1.87 (s,

2H), 1.92 - 2.04 (m, IH), 2.11 (t, IH), 2.25 (dd, IH), 2.70 (d, IH), 2.99 (d, IH), 3.67 (s, 2H), 4.25 (d, IH), 4.59 (s, 2H), 4.83 (d, IH), 4.92 (d, IH), 5.74 (s, IH), 6.79 (d, IH), 7.00 (d, IH), 7.28 (d, IH), 7.41 - 7.47 (m, IH), 7.48 - 7.54 (m, IH), 8.00 (d, IH), 11.20 (br s, IH).

Intermediate 7

3-((4-Aminopiρeridin-l-vDmethyl)-5-oxo-3,5-dihvdro-2H-ri,41oxazinor2.3.4-iilquinoline-10- carbonitrile, Enantiomer 1

and

Intermediate 8

3-(^"(^"4-Aminopiperidin-l-vDmethyl)-5-oxo-3,5-dihvdro-2H-ri.41oxazinor2.3.4-iilquinoline-10- carbonitrile, Enantiomer 2

A solution of tert-butyl l-((10-cyano-5-oxo-3,5-dihydro-2H-[l,4]oxazino[2,3,4-ij]quinolin-3- yi)methyi)piperidin-4-ylcarbamate (Intermediate 9, 250 mg, 0.59 mmol) in chloroform (20 mL) was stirred and cooled to 0 ⁰C. To this was added trifluoroacetic acid (1 mL, 13 mmol) dropwise over 10 minutes to give a pale yellow solution. This was allowed to warm to ambient temperature and stir overnight. The solution was concentrated, codistilled with methanol twice and dried under high vacuum. The resulting mixture of enantiomers was separated by chiral HPLC on a Chiralpak AD column (250 x 20 mm, 10 micron) eluting with 70:15:15:0.1 hexanes:ethanol:methanol:diethylamine at a flow rate of 20 mL/min. This gave 62 mg of 3-((4-aminopiperidin-l-yl)methyl)-5-oxo-3,5-dihydro-2H-[l,4]oxazino[2,3,4- ij]quinoline-10-carbonitrile, enantiomer 1 (Intermediate 7, first eluting enantiomer) and 54 mg of 3-((4-aminopiperidin-l-yl)methyl)-5-oxo-3,5-dihydro-2H-[l,4]oxazino[2,3,4- ij]quinoline-10-carbonitrile, enantiomer 2 (Intermediate 8, second eluting enantiomer,) both as colorless glasses. MS (ES): 325 (M+H⁺) for Ci₈H₂₀N₄O₂

¹H-NMR (DMSO-(U δ: 1.79 (d, 2H), 2.03 - 2.17 (m, 2H), 2.36 (m, 2H), 3.14 - 3.25 (m, 2H), 3.25 - 3.40 (m, 2H), 3.41 - 3.53 (m, IH), 3.95 (s, IH), 4.36 (d, IH), 4.91 (d, IH), 6.86 (d, IH), 7.49 - 7.56 (m, IH), 7.56 - 7.62 (m, IH), 8.08 (d, IH), 8.16 (br s, 2H).

Intermediate 9: fert-Butyl l-fri0-cvano-5-oxo-3,5-dihvdro-2H-[l,41oxazmor2,3,4-ii1quinolin-3- vDmethyl)piperidin-4-ylcarbamate

To a solution of 3-formyl-5-oxo-3,5-dihydro-2H-[l,4]oxazino[2,3,4-ij]quinoline-10- carbonitrile (Intermediate 10, 275 mg, 1.14 mmol) in dry THF (20 mL) was added tert-butyl piperidin-4-ylcarbamate (275 mg, 1.37 mmol) to give a yellow solution with stirring. After 45 minutes sodium triacetoxyborohydride (607 mg, 2.86 mmol) was added in one portion. The mixture was stirred at room temperature for 90 minutes, then quenched with methanol and concentrated. The residue was cliromatographed on silica gel with a gradient of 0 to 60% acetone in hexanes to give 250 mg (0.59 mmol, 51%) of the title compound as a colorless, foamy glass. MS (ES): 425 (M+H⁺) for C₂₃H₂₈N₄O₄

¹H-NMR (DMSO- dft δ: ppm: 1.36 (s, 9H) 1.65 (t, 2H) 1.93 - 2.05 (m, 2H) 2.05 - 2.17 (m, 2H), 2.24 (dd, 2H), 2.71 (dd, IH), 3.01 (d, IH), 3.17 (s, IH), 4.24 (dd, IH), 4.82 (d, IH), 4.92 (d, IH), 6.74 - 6.82 (m, 2H), 7.42 - 7.47 (m, IH), 7.48 - 7.54 (m, IH), 8.00 (d, IH).

Intermediate 10

3-Formyl-5-oxo-3,5-dihvdro-2H-ri.4]oxazinor2,3,4-iilquinoline-10-carbonitrile To a suspension of 3-(hydroxymethyl)-5-oxo-3,5-dihydro-2H-[l,4]oxazino[2,3,4-ij]quinoline- 10-carbonitrile (Intermediate 11, 0.59 g, 2.44 mmol) in 75 mL dichloromethane was added Dess-Martin periodinane (1,1,1 -tris(acetyloxy)- 1 , 1 -dihydro- 1 ,2-benziodoxol-3-(lH)-one) (1.24 g, 2.9 mmol) in one portion. The mixture was stirred for one hour, then diluted with dichloromethane. The organic phase was washed with a mixture of 10% sodium thiosulfate solution and saturated sodium bicarbonate solution (1:1, 2 x 50 mL), dried, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel with a gradient of hexanes/ ethyl acetate (4:1 to 1:4) to give 380 mg (65%) of the title compound as a pale orange foam. MS (ES): 241 (M+H⁺) for C₁₃H₈N₂O₃

¹H-NMR (DMSO- d;) δ: ppm 4.40 (dd, IH), 4.9 -5.1 (m, IH), 5.39 (d, IH), 6.84 (d, IH), 7.37 - 7.42 (m, IH), 7.5 - 7.6 (m, IH), 8.06 (d, IH), 9.72 (br s, IH).

Intermediate 11

3-(Hvdroxymethyl)-5-oxo-3,5-dihvdro-2H-ri,41oxazinor2,3,4-iilquinoline-10-carbonitrile A solution of 10-bromo-3-(hydroxymethyl)-2H-[l,4]oxazino[2,3,4-ij]quinolin-5(3H)-one (Intermediate 12, 1.0 g, 3.4 mmol) and copper (I) cyanide (0.33 g, 3.7 mmol) in dry N- methylpyrrolidinone (20 mL) was stirred and heated to 180 ⁰C overnight under nitrogen. The resulting light brown solution was cooled and poured into a mixture of ice water and concentrated ammonium hydroxide (1:1, 200 mL). The resulting dark mixture was stirred in an ice bath for three hours, then filtered and the filter cake washed with water. The filtrate was extracted with ethyl acetate (3 x 100 mL) and the combined organic phases were washed with water, then brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with a gradient of 0 to 40% acetonitrile in dichloromethane gave 0.59 g (71%) of the title compound as a pale orange solid. MS (ES): 243 (M+H⁺) for C₁₃Hi₀N₂O₃

¹H-NMR (DMSO- cU) δ: ppm 3.38 - 3.45 (m, IH), 3.51 (ddd, IH), 4.28 (dd, IH), 4.73 - 4.81 (m, IH), 4.88 (d, IH), 5.34 (t, IH), 6.81 (d, IH), 7.42 - 7.47 (m, IH), 7.48 - 7.54 (m, IH), 8.01 (d, IH).

Intermediate 12

10-Bromo-3-(hvdroxymethylV2H-[l,41oxazmo[2,3,4-iilquinolin-5(3HVone To a suspension of 7-bromo-8-hydroxyquinolin-2-one (Intermediate 13, 2.0 g, 8.3 mmol) in dry dioxane (30 mL) and dry DMF (15 mL) under dry nitrogen was added catalytic piperidine (O.lmL) with stirring to give a brown mixture. Epichlorohydrin (6.5 mL, 83.3 mmol) was added in one portion and the brown mixture heated to 85 ⁰C and stirred overnight. The brown solution was cooled, concentrated under reduced pressure and chromatographed on silica with a gradient of 10 to 70% ethyl acetate in hexanes to give 1.0 g (40%) of the title compound as a tan solid.

MS (ES): 296 / 298 (M+ϊt) for Ci₀Hi₀BrNO₃

¹H-NMR (DMSO-d^ δ: ppm: 3.49 (ddd, IH), 4.14 (dd, IH), 4.72 - 4.79 (m, IH), 4.83 (dd,

IH), 5.34 (dd, IH), 6.66 (d, IH), 7.25 - 7.29 (m, IH), 7.42 (d, IH), 7.94 (d, IH).

Intermediate 13

7-Bromo-8-hvdroxyquinolin-2riH)-one

A solution of 7-bromo-8-methoxyquinolin-2(lH)-one (Intermediate 14, 0.5 g, 1.97 mmol) in

48% aqueous HBr (15 mL) was heated to 135 ⁰C and stirred overnight, after which a tan solid had precipitated. The mixture was cooled to ambient temperature, poured into ice-water, filtered, and the solid washed with water until the filtrate was neutral. After air-drying, the solid was dried under vacuum to give 360 mg (76%) of the title compound as a tan solid.

MS (ES): 240 / 242 (M+H⁺) for C₉H₆BrNO₂

¹H-NMR fDMSO-d_c) δ: ppm 6.61 (d, IH); 6.87 (d, IH); 7.25 - 7.32 (m, IH); 7.90 - 7.97 (m,

IH); 10.76 (br s, 2H).

Intermediate 14

7-Bromo-8-methoxyqumolin-2(lH)-one

To 10 mL of concentrated sulfuric acid was added trans-N- (3-bromo-2-methoxyphenyl)-3- ethoxy-2-propenamide (Intermediate 15, 1.96 g, 6.5 mmol) in portions over 15 minutes to give a pale yellow solution which was stirred overnight at ambient temperature. The yellow solution was poured into ca. 300 mL ice-water to give a pale yellow precipitate, which was collected by filtration, washed with water and crystallized from 2-propanol to give 1.2 g

(73%) of the title compound as a colourless solid.

MSJES): 254 / 256 (M+Η⁺) for C₁₀H₈BrNO₂

¹H-NMR (DMSO-d^ δ: ppm 3.80 (s, 3H); 6.54 (d, IH); 7.38 (s, 2H); 7.90 (d, IH); 11.43 (s,

IH). Intermediate 15 frarø-N- (3-bromo-2-methoxyphenyiV3-ethoxy-2-propenamide

A solution of (E)-3-ethoxyacrylic acid (2.25 g, 19.4 mmol) in dry chloroform (100 mL) was cooled to 0 ⁰C with stirring and a 2M solution of oxalyl chloride in dichloromethane (19.4 mL, 38.8 mmol) was added slowly over five minutes. Catalytic N,N-dimethylformamide (1-2 drops) was added, and the resulting pale yellow solution was allowed to warm to ambient temperature, and then was heated to reflux during which a large amount of gas evolved. After stirring for one hour, the solution was cooled and concentrated, redissolved in 25 mL dry chloroform, and added slowly to a stirred, ice-cold solution of 3-bromo-2-methoxyaniline (Intermediate 16 (Prepared as described in J. Am. Chem. Soc. 56, 1934, 1787), 2.8 g, 13.9 mmol) and pyridine (3.4 mL, 41.6 mmol) in chloroform (75 mL). The pH of the resulting orange solution was adjusted to alkaline with additional pyridine, and the solution stirred at ambient temperature overnight. The resulting orange solution was washed 3x with IN HCl, once with saturated NaHCO₃ solution, then brine; dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel eluting with a gradient of 0 to 30% ethyl acetate in hexanes and concentration under reduced pressure gave the product as a yellow solid, which was recrystallized from 2-propanol / water to give 1.96 g (47%) of the title compound as off-white needles.

MSJES): 300 / 302 (M+H⁺) for Ci₂Hi₄BrNO₃ and 322.0 / 324.0 (M+Na*)

¹H-NMR fPMSO-d_c) δ: ppm 1.28 (t, 3H); 3.73 (s, 3H); 3.95 (q, 2H); 5.95 (d, IH); 7.03 (t,

IH); 7.30 (dd, IH); 7.49 (d, IH); 8.14 (dd, IH); 9.25 (s, IH).

Intermediate 16

3-Bromo-2-methoxyaniline

A suspension of l-bromo-2-methoxy-3-nitrobenzene (Intermediate 17, 4.45 g, 19.2 mmol) in

15 mL EtOH and 20 mL 30% NH₄OH solution was cooled to 0 ⁰C with stirring and zinc powder (6.3 g, 95.9 mmol) was added in portions to give a gray/yellow mixture. This was allowed to warm to ambient temperature and stirred for 2 hours. The mixture was filtered through Celite and the filter cake washed with EtOAc until the filtrate was colorless. The filtrate was washed with saturated NaHCO₃ solution, the aqueous phase was back-extracted with ethyl acetate. The combined organic phases were washed once with brine, dried over sodium sulfate and concentrated under reduced pressure to give a red/orange oil. Chromatography on silica gel eluting with a gradient of 0 to 30% ethyl acetate in hexanes gave 2.8 g (73%) of the title compound as an orange oil.

MS (ES): 202 / 204 (M+ϊt) for C₇H₈BrNO

¹H-NMR fCDCU δ: ppm 3.82 (s, 3H); 3.85 (s, 2H); 6.64 - 6.69 (m, IH); 6.77 (t, IH); 6.87 -

6.92 (m, IH).

Intermediate 17 l-Bromo-2-methoxy-3-nitrobenzene

To a mixture of 2-bromo-6-nitrophenol (5.0 g, 22.9 mmol) and potassium carbonate (6.3 g,

45.8 mmol) in acetone (100 mL) was added iodomethane (2.85 mL, 45.8 mmol) under stirring and the mixture was then heated to reflux overnight. The mixture was cooled to room temperature, filtered through Celite, the filter cake washed with ethyl acetate, and the filtrate concentrated under reduced pressure. The residue was taken up in ethyl acetate, washed 3x with IN NaOH, once with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized twice from 2-propanol / water to give 4.45 g (83.6%) of the title compound as beige, very fine needles.

MS (ESI: 232 / 234 (M+H⁺) for C₇H₆BrNO

¹H-NMR (DMSO-d^ δ: ppm 3.98 (s, 3H); 7.39 (t, IH); 8.02 (dd, IH); 8.08 (dd, IH).

Example 4

10-Methoxy-3-(^"(4-(r3-oxo-3,4-dihvdro-2H-pyridor3.2-biri.41oxazin-6- vDmethylamino)piperidin-l-yl)methyl')-2H-[l,41oxazino[2,3,4-iilquinolin-5(3H)-one A solution of 3-((4-ammopiperidin-l-yl)methyl)-10-methoxy-2H-[l,4]oxazino[2,3,4- ij]quinolin-5(3Η)-one (Intermediate 18, 0.17 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2- &][l,4]oxazine-6-carboxaldehyde (37 mg, 0.21 mmol) in TΗF (5 mL) was stirred for 90 minutes at room temperature, then sodium triacetoxyborohydride (92 mg, 0.43 mmol) was added in one portion and the mixture stirred for four hours. The reaction was quenched with the addition of methanol and the mixture concentrated under reduced pressure. Chromatography was done on silica gel eluting with a gradient of 100% dichloromethane going to 10% methanol in dichloromethane to give 46 mg (0.09 mmol, 53%) of the title compound as a mixture of enantiomers in the form of a colourless solid. MS (ES): 492 (MH⁺) for C₂₆H₂₉N₅O₅ ¹H-NMR (MeOD-(J₁ ^') δ: ppm 1.47 - 1.60 (m, 2H), 1.77 (s, 2H), 1.87 - 2.01 (m, 2H), 2.01 -

2.09 (m IH), 2.10 - 2.18 (m, IH), 2.25 (dd, IH), 2.49 (dd, IH), 2.80 - 2.94 (m, 2H)₅ 3.11 (d, IH), 3.79 (s, 3H), 3.86 (dd, IH), 3.99 (s, 2H), 4.53 (s, 2H), 4.69 (d, IH), 4.85 (d, IH), 6.33 (d, IH), 6.86 - 6.94 (m, 2H), 7.11 - 7.21 (m, 2H), 7.69 (d, IH).

The R and S enantiomers of the title compound of Example 4 may be separated by chiral chromatography, using a procedure similar to the one described for the separation of Interemediates 7 and 8.

Intermediate 18

3 -(Y4-Aminopiperidin- 1 -vDmethyl)- 10-methoxy-2H-[ 1.4^"loxazino [2,3 ,4-ii]qumol-n-5(3Η)-one A solution of tert-butyl l-((10-methoxy-5-oxo-3,5-dihydro-2H-[l,4]oxazino[2,3,4-ij]quinolin- 3-yl)methyl)piperidin-4-ylcarbamate (Intermediate 19, 70 mg, 0.16 mmol) in methanol (10 mL) was stirred and cooled to 0 ⁰C. To this was added 6N hydrochloric acid (0.5 mL, 3 mmol) dropwise over 5 minutes to give a colorless solution. This was allowed to warm to ambient temperature then heated to reflux for 60 minutes. The solution was concentrated, codistilled with methanol twice, then placed under vacuum overnight to give 70 mg (0.17 mmol, 107%) of the bis hydrochloride salt of the title compound as an off-white solid. The bis hydrochloride salt was dissolved in saturated sodium bicarbonate solution (1 mL), and extracting with dichloromethane (three times 10 mL). The combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The free base of the crude product was taken to the next step without further purification. MS (ES): 330.2 (MH⁺) for Ci₈H₂₃N₃O₃

¹H-NMR (MeOD-d/P δ: 2.03 (s, IH), 2.11 (s, IH), 2.20 - 2.32 (m, 2H), 2.38 (d, IH), 3.34 (s,

3H), 3.43 - 3.57 (m, 3H), 3.63 - 3.78 (m, 2H), 3.94 (s, 3H), 4.12 (d, IH), 4.40 (d, IH), 5.45 (d, IH), 6.57 (d, IH), 7.11 (d, IH), 7.39 (d, IH), 7.94 (d, IH).

Intermediate 19 tert-Butyl l-((10-methoxy-5-oxo-3,5-dihvdro-2H-[l,41oxazinor2,3,4-iilquinolm-3- yl)methyl)piperidin-4-ylcarbamate

A mixture of 10-methoxy-5-oxo-3,5-dihydro-2H-[l,4]oxazino[2,3,4-ij]quinoline-3- carbaldehyde (Intermediate 20, 70 mg, 0.29 mmol) and tert-butyl piperidin-4-ylcarbamate (69 mg, 0.34 mmol) in dry TΗF (10 mL) was stirred at room temperature for 90 minutes. Sodium triacetoxyborohydride (150 mg, 0.71 mmol) was added in one portion and the mixture was stirred at room temperature for 90 minutes, then quenched with methanol and concentrated. The residue was chromatographed on silica gel eluting with a gradient from 100% hexanes to 70% hexanes / 30% acetone to give 70 mg (0.16 mmol, 51%) of the title compound as a colorless hard foam. MS (ES): 430 (MH⁺) for C₂₃H₃IN₃O₅

¹H-NMR TCDCl₃) δ: ppm: 1.43 (m, HH), 1.93 (s, 3H), 2.23 - 2.38 (m, 2H), 2.40 (s, 2H),

2.88 (br s, IH), 3.48 (s, 2H), 3.93 - 4.03 (m, 4H) 4.45 (s, IH), 4.97 (s, IH), 6.51 (d, IH), 6.86 (d, IH), 7.14 (d, IH), 7.62 (d, IH).

Intermediate 20

10-Methoxy-5-oxo-3,5-dihydro-2H-|^'L41oxazinor2,3,4-ii1quinoline-3-carbaldehyde To a suspension of 3-(hydroxymethyl)-10-methoxy-2Η-[l,4]oxazino[2,3,4-ij]quinolin-5(3H)-one (Intermediate 21, 0.15 g, 0.6 mmol) in dichloromethane (10 mL) was added Dess-Martin periodinane (0.34 g, 0.8 mmol) in one portion with stirring. The mixture was stirred at ambient temperature overnight, then diluted with dichloromethane and washed with a 1:1 mixture of 10% sodium thiosulfate (Na₂O₃S₂) solution and saturated sodium bicarbonate solution (2 x 5OmL), dried over sodium sulfate and concentrated under reduced pressure. Chromatography was done on silica eluting with a gradient of 0 to 40% acetonitrile in dichloromethane to give 70 mg (0.29 mmol, 48%) of the title compound as a tan solid. MS (ES): 246 (MH⁺) for C_I3H_HNO₄

¹H-NMR (ODCl₃) δ: ppm 3.94 (s, 3H), 4.20 (dd,lH), 5.13 (dd, IH), 5.51 (dd, IH), 6.58 (d, IH), 6.87 (d, IH), 7.21 (d, IH), 7.71 (d, IH), 9.61 (s, IH).

Intermediate 21

3-(Hvdroxyme1hyl)-10-methoxy-2H-ri,41oxazinor2.3.4-iilquinolin-5(3H)-one A solution of sodium methoxide in methanol was prepared by adding sodium metal (195 mg, 8.4 mmol (which had been previously washed with hexanes, then very briefly with dry methanol to remove the oxidized exterior) to 6 mL of dry methanol under dry N₂ to give a colorless mixture. This was stirred at 0 ⁰C until dissolution of the sodium was complete. The colorless solution of sodium methoxide was cannulated into a stirring mixture of 10-bromo-3- (hydroxymethyl)-2Η-[l,4]oxazino[2,3,4-ij]quinolin-5(3Η)-one (Intermediate 12, 0.5 g, 1.7 mmol) and copper (I) iodide (0.16 g, 0.84 mmol) in 6 mL dry N,N-dimethylformamide under dry N₂ to give a yellow solution. This mixture was heated to 140 ⁰C for two hours, filtered through Celite, and the filter cake washed with dichloromethane. The filtrate and wash was diluted with an additional 100 mL dichloromethane, washed once with 50 mL of a 5% citric acid solution, once with 50 mL of a saturated sodium bicarbonate solution, then brine, dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel eluting with a gradient from 20% to 60% acetonitrile in dichloromethane gave 0.15 g (0.6 mmol, 36%) of the title compound as a tan solid. MS (ES): 248 (MH⁺) for Ci₃Hi₃NO₄ 1H-NMR (CDCL) δ: ppm 3.40 (m, IH), 3.82 - 3.94 (m, 2H), 3.97 (s, 3H), 4.07 (dd, IH), 4.83

(dd, IH), 5.05 - 5.16 (m, IH), 6.55 (d, IH), 6.89 (d, IH), 7.18 (d, IH), 7.66 (d, IH).

Claims

What is claimed is:

1. A compound of Formula (I):

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is selected from H, halo, -CN, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^la, -SR^la, -N(R^la)₂, -N(R^la)C(O)R^lb, -N(R^la)N(R^la)₂, -C(O)H, -C(O)R^lb, -C(O)₂R^la, -C(O)N(R^la)₂, -OC(O)N(R^la)₂, -N(R^la)C(O)₂R^la, -N(R^la)C(O)N(R^la)₂, -OC(O)R^lb, -S(O)R^lb, -S(O)₂R^lb, -S(O)₂N(R^la)₂, -N(R^la)S(O)₂R^lb, -C(R^la)-N(R^la), and -C(R^la)=N(0R^la), wherein said Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R¹⁰;

R^la in each occurrence is independently selected from H, C^alkyl, carbocyclyl, and lieterocyclyl, wherein said Ci-βalkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R¹⁰;

R^lb in each occurrence is independently selected from C^alkyL C_2-6alkenyl,

C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, C_2-6alkenyl,

C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R¹⁰;

R² is selected from H, halo, -CN, C^aUcyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^2a, -SR^2a, -N(R^2a)₂, -N(R^2a)C(O)R^2b, -N(R^2a)N(R^2a)₂, -C(O)H,

-C(O)R^2b, -C(O)₂R^2a, -C(O)N(R^2a)_2; -OC(O)N(R^2a)₂, -N(R^2a)C(O)₂R^2a,

-N(R^2a)C(O)N(R^2a)₂, -OC(O)R^2b, -S(O)R^2b, -S(O)₂R^2b, -S(O)₂N(R^2a)₂,

-N(R^2a)S(O)₂R^2b, -C(R^2a)=N(R^2a), and -C(R^2a)=N(OR^2a), wherein said Ci_-6alkyl,

C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R²⁰;

R^2a in each occurrence is independently selected from H, Ci-βalkyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R²⁰;

R^2b in each occurrence is independently selected from Ci.galkyl, C_2-6alkenyl,

C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^alkyl, C_2-6alkenyl,

C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R²⁰;

R³ is selected from H, halo, -CN, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^3a, -SR^3a, -N(R^3a)₂, - -N(R^3a)N(R^3a)₂, -C(O)R^3b, , -C(O)N(R^3a)₂,

-OC(O)N(R^3a)₂, -N(R^3a)C(O)₂R^3a, -N(R^3a)C(O)N(R^3a)₂, -OC(O)R^3b, -S(O)R^3b,

-S(O)₂R³⁵, -N(R^3a)S(O)₂R^3b, -C(R^3a)=N(R^3a), and -C(R^3a)=N(OR^3a), wherein said d-βalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R³⁰;

R^3a in each occurrence is independently selected from H, C_halky., carbocyclyl, and heterocyclyl, wherein said Ci.βalkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R³⁰;

R^3b in each occurrence is independently selected from Ci_-6alkyl, C_2-6alkenyl,

C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R³⁰;

R⁴ in each occurrence is independently selected from halo, -CN, Ci^alkyl, C_2-6alkenyl,

C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^4a, -SR^4a, -N(R^4a)₂, -N(R^4a)C(O)R^4b,

-C(O)H, -C(O)R^4b, -C(O)₂R^4a, -C(O)N(R^4a)₂, -OC(O)N(R^4a)₂, -N(R^4a)C(O)₂R^4a,

-N(R^4a)C(O)N(R^4a)₂, -OC(O)R^4b, -S(O)R^4b, -S(O)₂R^4b, -S(O)₂N(R^4a)₂,

-N(R^4a)S(O)₂R^4b, -C(R^4a)=N(R^4a), and -C(R^4a)=N(OR^4a), wherein said C_1-6alkyl,

C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R⁴⁰, or two R⁴ substituents on the 2 and 6 carbon atoms optionally may together form an ethylene bridge;

R^4a in each occurrence is independently selected from H,

carbocyclyl, and heterocyclyl, wherein said Ci^alkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R⁴⁰;

R^4b in each occurrence is independently selected from C^aUcyl, C_2-6alkenyl,

C₂-₆alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R⁴⁰;

R⁵ is selected from H, halo, -CN, C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^5a, -SR^5a, -N(R^5a)₂, -N(R^5a)C(O)R^5b, -N(R^5a)N(R^5a)₂, -C(O)H,

-C(O)R^5b, -C(O)₂R⁵³, -C(O)N(R^5a)₂, -OC(O)N(R^5a)₂, -N(R^5a)C(O)₂R^5a,

-N(R^5a)C(O)N(R^5a)₂, -OC(O)R^5b, -S(O)R^5b, -S(O)₂R⁵", -S(O)₂N(R^5a)₂,

-N(R^5a)S(O)₂R^5b, -C(R^5a)=N(R^5a), and -C(R^5a)=N(OR^5a), wherein said Ci_-6alkyl,

C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are optionally substituted with one or more R⁵⁰;

R^Sa in each occurrence is independently selected from H, Cμβalkyl, carbocyclyl, and heterocyclyl, wherein said C^aUcyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R⁵⁰;

R^5b in each occurrence is independently selected from C_1-6alkyl, C_2-6alkenyl,

C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R⁵⁰;

R⁶ and R⁷ are each hydrogen, or R⁶ and R⁷ together form =0; R¹⁰ in each occurrence is independently selected from halo, -CN, Q-βalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^10a, -SR^1Oa, -N(R^10a)₂, -N(R^10a)C(O)R^10b, -N(R^10a)N(R^10a)₂, -C(O)H, -C(O)R^10b, -C(O)₂R^10a, -C(O)N(R^10a)₂, -OC(O)N(R^10a)₂, -N(R^10a)C(O)₂R^10a, -N(R^10a)C(O)N(R^10a)₂, -OC(O)R^10b, -S(O)R^10b, -S(O)₂R^10b, -S(O)₂N(R^10a)₂, -N(R^10a)S(O)₂R^10b, -C(R^1Oa)=N(R^1Oa), and -C(R^10a)=N(OR^10a), wherein said Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^a; R^1Oa in each occurrence is independently selected from H, Ci-6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci-βalkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^a;

R^1Ob in each occurrence is independently selected from

C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^aUcyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^a;

R²⁰ in each occurrence is independently selected from halo, -CN, Ci-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^20a, -SR^20a, -N(R^2Oa)₂, -N(R^20a)C(O)R^20b, -N(R^20a)N(R^20a)₂, -C(O)H, -C(O)R^20b, -C(O)₂R^20a, -C(O)N(R^20a)₂, -OC(O)N(R^20a)₂, -N(R^20a)C(O)₂R^20a, -N(R^20a)C(O)N(R^20a)₂, -OC(O)R^20b, -S(O)R^20b, -S(O)₂R^20b, -S(O)₂N(R^20a)₂, -N(R^20a)S(O)₂R^20b, -C(R^20a)=N(R^20a), and -C(R^20a)=N(OR^20a), wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyI, carbocyclyl, and heterocyclyl are each, independently and optionally substituted with one or more R^b; R^20a in each occurrence is independently selected from H, Q^alkyl, carbocyclyl, and heterocyclyl, wherein said C^aUcyl, carbocyclyl, and heterocyclyl are each, independently and optionally substituted with one or more R^b;

R^20b in each occurrence is independently selected from Cμgalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C_1-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^b;

- R³⁰ in each occurrence is independently selected from halo, -CN, C^aUcyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^30a, -SR^3Oa, -N(R^30a)₂, -N(R^30a)C(O)R^30b, -N(R^30a)N(R^30a)₂, -C(O)H, -C(O)R^30b, -C(O)₂R^30a, -C(O)N(R^30a)₂, -OC(O)N(R^30a)₂, -N(R^30a)C(O)₂R^30a, -N(R^30a)C(O)N(R3^10a)₂, -OC(O)R^30b, -S(O)R^30b, -S(O)₂R^30b, -S(O)₂N(R^30a)₂, -N(R^30a)S(O)₂R^30b, -C(R^3Oa)=N(R^3Oa), and -C(R^30a)=N(OR^30a), wherein said Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R°; R^3Oa in each occurrence is independently selected from H, C_1-6alkyl, carbocyclyl, and heterocyclyl, wherein said Q-όalkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^c;

R^30b in each occurrence is independently selected from Ci-βalkyl, C_2-6alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl, wherein said Ci_₆alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R°;

R⁴⁰ in each occurrence is independently selected from halo, -CN, Ci-βalkyl, C_2-6alkenyl, C₂.₆alkynyl, carbocyclyl, heterocyclyl, -OR^40a, -SR^40a, -N(R^40a)₂, -N(R^40a)C(O)R^40b, -N(R^4Oa)N(R^4Oa)₂, -C(O)H, -C(O)R^40b, -C(O)₂R^40a, -C(O)N(R^40a)₂, -OC(O)N(R^40a)₂, -N(R^40a)C(O)₂R^40a, -N(R^40a)C(O)N(R^40a)₂, -OC(O)R^40b, -S(O)R^40b, -S(O)₂R⁴⁰", -S(O)₂N(R^40a)₂, -N(R^40a)S(O)₂R^40b, -C(R^40a)=N(R^40a), and -C(R^40a)=N(OR^40a), wherein said Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^d; R^40a in each occurrence is independently selected from H, C_halky!, carbocyclyl, and heterocyclyl, wherein said C^aUcyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^d;

R^40b in each occurrence is independently selected from C^aHcyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C^alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally substituted with one or more R^d;

R⁵⁰ in each occurrence is independently selected from halo, -CN, Ci-_δalkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^50a, -SR^50a, -N(R^50a)₂, -N(R^50a)C(O)R^50b, -N(R^50a)N(R^50a)₂, -C(O)H, -C(O)R^50b, -C(O)₂R^50a, -C(O)N(R^50a)₂, -OC(O)N(R^50a)₂, -N(R^50a)C(O)₂R^50a, -N(R^50a)C(O)N(R^50a)₂, -OC(O)R^50b, -S(O)R^50b, -S(O)₂R^50b, -S(O)₂N(R^50a)₂, -N(R^50a)S(O)₂R^50b, -C(R^50a)=N(R^50a), and -C(R^50a)=N(OR^50a), wherein said Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^e; R^50a in each occurrence is independently selected from H, C_1-6alkyl, carbocyclyl, and heterocyclyl, wherein said Ci-ealkyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^e; R^5Ob in each occurrence is independently selected from Ci^alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, and heterocyclyl, wherein said C_1-6alkyl, C_2-6alkenyl, C₂-₆alkynyl, carbocyclyl, and heterocyclyl are each, independently and optionally, substituted with one or more R^e;

R^a, R^b, R^c, R^d, and R^e in each occurrence are independently selected from halo, -CN, Ci_-6alkyl, C_2-6alkenyl, C_2-6alkynyl, carbocyclyl, heterocyclyl, -OR^m, -SR^m, -N(R^m)₂, -N(R^m)C(O)Rⁿ, -N(R^m)N(R^m)₂, -C(O)H, -C(O)R", -C(O)₂R^m, -C(O)N(R^m)₂, -OC(O)N(R^m)₂, -N(R^m)C(O)₂R^m, -N(R^m)C(O)N(R^m)₂, -OC(O)R⁰, -S(O)R", -S(O)₂R", -S(O)₂N(R^m)₂, -N(R^m)S(O)₂R", -C(R^m)=N(R^m), and -C(R^ra)=N(0R^ra); R^m in each occurrence is independently selected from H and Ci-βalkyl; Rⁿ in each occurrence is C^aUcyl; and n is selected from O, 1, 2, and 3.

2. A compound of Formula (I) as claimed in claim 1, wherein the compound is of Formula (Ia):

Formula (Ia)

or a pharmaceutically acceptable salt thereof, wherein X, R¹, R², R³, R⁴, and n are as defined in claim 1.

3. A compound of Formula (I), wherein the compound is of Formula (Ia):

Formula (Ib) or a pharmaceutically acceptable salt thereof, wherein X, R¹, R², R³, R⁴, and n are as defined in claim 1.

4. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3, wherein X is O.

5. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4, wherein R¹ is H.

6. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5, wherein R² is H.

7. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 6, wherein R³ is selected from halo, -CN, and -OR^3a; and

R ,3^Ja^a is Ci_-6alkyl.

A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 7, wherein n is 0.

. A compound of Formula (I):

Formula (I)

or a pharmaceutically acceptable salt thereof, wherein A, D, G, E, R⁶, and R⁷, together with the ring atoms to which they are attached form a group selected from:

X is O; R¹ is H; R² is H;

R³ is selected from fluoro, -CN, and methoxy; and n is 0.

10. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, for use as a medicament.

11. The use of a compound of Formula (I)₃ or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for use in the treatment of a bacterial infection in a warm-blooded animal such as man.

12. The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for use in the treatment of a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragϊlis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabϊlis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophyticus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man.

13. The use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, in the manufacture of a medicament for use in the treatment of an infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warmblooded animal such as man.

14. A method for treating a bacterial infection in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of formula (I), as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

15. A method for treating a bacterial infection caused by one or more pathogenic organisms such as Acinetobacter baumanii, Aeromis hydrophila, Bacillus anthracis, Bacteroides fragilis, Bordatella pertussis, Burkholderia cepacia, Chlamyida pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusobacterium necrophorum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus somnus, Klebsiella oxytoca, Klebsiella pneumoniae, Legionella pneumophila, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Proteus vulgaris, Pseudomonas aeruginosa, Salmonella typhi, Salmonella typhimurium, Serratia marcesens, Shigella flexneria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus intermedius, Staphylococcus saprophytics, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, and Streptococcus pyrogenes, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

16. A method for treating a bacterial infection such as bronchitis, C. difficile colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation Anthrax, intra-abdominal infections, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections, and urinary tract infections, in a warm-blooded animal such as man, said method comprising administering to said animal an effective amount of a compound of Formula (I), as claimed in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

17. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, for use in treating a bacterial infection in a warm-blooded animal, such as man.

18. A pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

19. A process for preparing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 9, said process comprising reacting a compound of Formula (ID):

Formula (ID)

with a compound of Formula (IE):

Formula (IE)